Aminoglycosides (gentamicin, amikacin, tobramycin, and neomycin): increased risk of deafness in patients with mitochondrial mutations

Evidence suggests an increased risk of aminoglycoside-associated ototoxicity in patients with mitochondrial mutations, including cases in which the patient’s aminoglycoside serum levels were within the recommended range. These mitochondrial mutations are rare and penetrance is uncertain. Genetic testing should not delay urgently needed aminoglycoside treatment but may be considered, especially before the start of recurrent or long-term treatment.

From:
Medicines and Healthcare products Regulatory Agency
Published
7 January 2021
Therapeutic area:
Infectious disease

Advice for healthcare professionals:

  • aminoglycoside use can result in rare cases of ototoxicity; some evidence suggests an association between mitochondrial mutations (particularly the m.1555A>G mutation) with an increased risk of this ototoxicity
  • some cases reported ototoxicity in patients with mitochondrial mutations who had aminoglycoside serum levels within the recommended ranges
  • these mitochondrial mutations are rare, and the penetrance of the observed increased ototoxic effect is unknown
  • consider the need for genetic testing especially in patients, particularly in those requiring recurrent or long-term treatment with aminoglycosides, but do not delay urgent treatment in order to test
  • when making prescribing decisions in patients with susceptible mutations, consider the need for aminoglycoside treatment versus alternative options available
  • to minimise the risks of adverse events, including ototoxicity, continuous monitoring (before, during and after treatment) of renal function (serum creatinine, creatinine clearance) and auditory function, as well as hepatic and laboratory parameters, is recommended for all patients
  • patients with known mitochondrial mutations or a family history of ototoxicity are advised to inform their doctor or pharmacist before they take an aminoglycoside
  • report suspected adverse reactions experienced to the Yellow Card scheme

Reminder of the risk of ototoxicity with aminoglycosides

Aminoglycosides are broad-spectrum bactericidal antibiotics. The group includes gentamicin, amikacin, tobramycin, and neomycin.

There is a narrow therapeutic window for aminoglycosides and their use can result in toxicity, including nephrotoxicity and ototoxicity, which can result in permanent hearing loss. This effect is related to the dose and duration of treatment and is exacerbated by renal or hepatic impairment or both and is more likely in elderly people and newborn babies.

To minimise the risk of ototoxicity with systemic aminoglycosides, regular serum concentration monitoring is recommended to maintain aminoglycoside levels below the toxic threshold for the cochleo-vestibular system. The product information for each medicine provides dosing considerations and recommendations for toxicity thresholds.

Assessment of auditory, vestibular, and renal function is particularly necessary in patients with additional risk factors.

Review of mitochondrial mutations and aminoglycoside ototoxicity

In 2020, we conducted a safety review following concerns received about the impact of mitochondrial mutations on the risk of ototoxicity with aminoglycosides. We identified several published epidemiological studies showing an increased risk of deafness in patients with the m.1555A>G mutation who were given aminoglycosides. There have also been reported cases of deafness in m.1555A>G patients with aminoglycoside use within the recommended serum levels. Some cases were associated with a maternal history of deafness or mitochondrial mutations or both.

Although no cases were identified with neomycin or topical preparations of gentamicin, amikacin, or tobramycin, based on a shared mechanism of action there is the potential for a similar effect with neomycin and other aminoglycosides that are administered at the site of toxicity (the ear).

The m.1555A>G mutation is the most common mitochondrial DNA (mtDNA) mutation, with an estimated prevalence of 0.2% in the general population.[footnote 1] The mutation is associated with sensorineural deafness and occurs in families with maternally transmitted deafness.

Clinicians should follow local guidelines on mitochondrial mutation screening in patients with a maternal history of deafness or mitochondrial mutations or both and who require aminoglycoside therapy. Genetic screening may be especially appropriate in patients requiring recurrent or long-term aminoglycoside therapy where the risk of ototoxicity is increased.

Evidence and case reports

Our review focused on four key epidemiological studies[footnote 1] [footnote 2] [footnote 3] [footnote 4] that reported an association between having mitochondrial mutations and an increased risk of deafness with aminoglycoside use. In addition, 10 case reports were identified from the medical literature indicating this toxicity. This evidence is further supported by a plausible biological mechanism where mutated mitochondrial ribosome more closely resembles the bacterial ribosome and may provide a binding site for aminoglycosides; this effect has been shown in biochemical tests.[footnote 5]

While many of the epidemiological studies had weak statistical power due to the rarity of the mitochondrial mutations, the evidence is considered sufficient to update the product information for aminoglycoside products with systemic absorption or that are administered at the site of toxicity (the ear).

The product information will be updated to include warnings of a potentially increased risk of ototoxicity in patients with known mitochondrial mutations. The patient information leaflet will ask patients to talk to their doctor or pharmacist before taking this medicine if they know (or think they have) a mitochondrial disease.

These mitochondrial mutations are rare, and the penetrance of the observed increased ototoxic effect is unknown. For patients known to have susceptible mutations, it is important to consider the need for aminoglycoside treatment and the alternative treatment options available when making prescribing decisions.

Report suspected adverse drug reactions on a Yellow Card

Any suspected adverse drug reactions to aminoglycosides should be reported to us on a Yellow Card.

Healthcare professionals, patients, and caregivers are asked to submit reports using the Yellow Card scheme electronically using:

When reporting please provide as much information as possible, including information about batch numbers, medical history, any concomitant medication, onset, treatment dates, and product brand name.

Report suspected side effects to medicines, vaccines or medical device and diagnostic adverse incidents used in coronavirus (COVID-19) using the dedicated Coronavirus Yellow Card reporting site or the Yellow Card app. See the MHRA website for the latest information on medicines and vaccines for COVID-19.

Article citation: Drug Safety Update volume 14, issue 6: January 2021: 6.

  1. Göpel W and others. ‘Mitochondrial mutation m. 1555A> G as a risk factor for failed newborn hearing screening in a large cohort of preterm infants’. BMC Pediatrics 2014; volume 14: number 210 (viewed 1 May 2020). ↩ ↩2

  2. Ealy M and others. ‘The prevalence of mitochondrial mutations associated with aminoglycoside-induced sensorineural hearing loss in an NICU population’. Laryngoscope 2011; volume 121; pages 1184–86 (viewed 1 May 2020). ↩

  3. Estivill X and others. ‘Familial progressive sensorineural deafness is mainly due to the mtDNA A1555G mutation and is enhanced by treatment with aminoglycosides’. The American Journal of Human Genetics 1998; volume 62: pages 27–35 (viewed 1 May 2020). ↩

  4. Johnson RF and others. ‘Genetic mutations and aminoglycoside-induced ototoxicity in neonates’. Otolaryngol Head Neck Surg 2010; volume 142: pages 704–07 (viewed 1 May 2020). ↩

  5. Gao Z and others. ‘Mitochondrial DNA mutations associated with aminoglycoside induced ototoxicity’. Journal of Otology 2017; volume 12: pages 1–8 (viewed 1 May 2020). ↩

Published 7 January 2021
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